Abstract

2,2,2-trifluoroethanol (TFE) is a commonly used cosolvent in experimental studies of peptides and proteins. Although concentration-dependent TFE effects have been well studied experimentally, the exact mechanism by which TFE affects the solubility and stability of peptides is still unclear. Here we report molecular dynamics simulations of TFE/water mixtures of different composition in an attempt to improve our atomic level understanding of the properties of TFE/water mixtures. The trends in most properties—densities, diffusion constants, dielectric constants, and enthalpies of mixing—were well reproduced, although quantitative agreement with experiment was poor. Other thermodynamic properties of the solutions—partial molar volumes, derivatives of activity coefficients, and isothermal compressibilities—were also determined using the Kirkwood–Buff theory of mixtures. The Kirkwood–Buff analysis indicated significant aggregation of TFE molecules in the mixtures, especially at low mole fractions, in agreement with experiment. However, the aggregation of TFE molecules was exaggerated using the current TFE and water models. The results suggest that the combination of simulation data and Kirkwood–Buff theory provides a powerful tool for the investigation of the thermodynamic properties of hydrogen bonding mixtures.